Study could help to settle controversy about insulin use in type 2 diabetes

For decades, medical researchers have debated whether insulin can promote atherosclerosis, the buildup of cholesterol in blood vessels that causes coronary artery disease and stroke. This was no theoretical argument for those patients with type 2 diabetes who need insulin injections to control their blood glucose levels.

Joslin researchers now have produced clear evidence that insulin protects arteries. “These results are definitive, at least in animals,” says George L. King, M.D., Joslin’s Chief Scientific Officer and senior author on a paper reporting the study published on May 5 in Cell Metabolism online.

Extrapolating the findings to humans would suggest that physicians should not be so wary of prescribing insulin to patients with diabetes, suggests Dr. King, who heads Joslin’s Dianne Nunnally Hoppes Laboratory for Diabetes Complications and is a Professor of Medicine at Harvard Medical School.

“It also raises the exciting possibility of designing special insulins that interact directly with blood vessels, potentially slowing atherosclerosis in these patients,” Dr. King speculates.

The study focuses on endothelial cells, the cells lining the inside of blood vessels in which atherosclerotic plaques develop.

The scientists began with a line of mice in which the gene for the insulin receptor has been knocked out in endothelial cells only. In these mice, endothelial cells are unresponsive to insulin.

“Mice don’t get atherosclerosis unless their normal cholesterol metabolism is changed,” notes Christian Rask-Madsen, M.D., Ph.D., a research associate in the Nunnally Hoppes lab and lead author on the paper. So the insulin-receptor knockout mice were crossed with another line of mice, known as ApoE mice, which has elevated cholesterol levels in the blood. Dr. Rask-Madsen and his colleagues then compared how atherosclerosis developed in these mice compared to standard ApoE mice.

The two groups of mice showed similar levels of other factors known to promote cardiovascular disease, including blood pressure, glucose metabolism and the levels of lipids in the blood.

But the scientists found that the insulin-receptor knockout mice were on a fast track to atherosclerosis. The insulin-receptor knockout mice developed cholesterol plaques that were more than twice the size of those found in the control animals.

The researchers also found a reason for the increased rate of artery damage. The endothelial cells in insulin-receptor knockout mice expressed more of the VCAM-1 adhesion molecule that helps white blood cells grab onto the growing plaques, and blood vessels gathered four times as many white blood cells. This condition was reversed when a VCAM-1 antibody was administered.

Taken altogether, the evidence “suggests that if you can improve insulin action in endothelial cells, you may be able to slow or prevent atherosclerosis,” Dr. Rask-Madsen notes.

In recent years, research at Joslin and elsewhere has shown that insulin resistance may work differently in different cell types. “It’s important not just to study its effect on glucose metabolism,” Dr. Rask-Madsen adds. “In type 1 diabetes, controlling blood glucose has been shown to be the main way to control late-stage complications. But we’ve had much less success improving long-term outcomes with type 2 diabetes. If we understand the special features of insulin resistance in endothelial cells, we may be able to find more effective treatments against artery damage and cardiovascular disease in people with diabetes.”

Funding for the research was led by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Iacocca Foundation, the Danish Medical Research Council and the Danish Heart Foundation.